Title | Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY |
Journal | Nature |
Volume | 504 |
Issue | 7480 |
Pagination | 451-5 |
Date Published | 2013 Dec 19 |
ISSN | 1476-4687 |
Keywords | Acetylation, Animals, Butyrates, Cell Differentiation, Cytokines, Dendritic Cells, Enhancer Elements, Genetic, Fermentation, Forkhead Transcription Factors, Histone Deacetylases, Inflammation Mediators, Intestinal Mucosa, Intestines, Introns, Lymphocyte Count, Male, Mice, Mice, Inbred C57BL, Starch, Symbiosis, T-Lymphocytes, Regulatory |
Abstract | Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the composition of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells, the molecular cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, we reasoned that their metabolic by-products are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. We tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory Treg cells. We found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermentation, facilitated extrathymic generation of Treg cells. A boost in Treg-cell numbers after provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells, as the observed phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic Treg-cell differentiation. In addition to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. Our results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms. |
DOI | 10.1038/nature12726 |
Alternate Journal | Nature |
PubMed ID | 24226773 |
PubMed Central ID | PMC3869884 |
Grant List | R37AI034206 / AI / NIAID NIH HHS / United States T32A1007621 / / PHS HHS / United States T32 CA009149 / CA / NCI NIH HHS / United States T32 AI007621 / AI / NIAID NIH HHS / United States P30 CA008748 / CA / NCI NIH HHS / United States R37 AI034206 / AI / NIAID NIH HHS / United States / / Howard Hughes Medical Institute / United States T32 GM007739 / GM / NIGMS NIH HHS / United States |
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